TB and HIV: An introduction for journalists

E Jane Carter, MD President, International Union Against TB and Lung Disease Associate Professor, Warren Alpert School of Medicine at Brown University Providence, Rhode Island USA

Presentation Outline
Unique Symbiosis of the two epidemics Diagnosis
HIV in TB patients TB in HIV patients

Treatment
Timing of therapy for each Drug Interactions and Compatibilities IRIS

Programmatic support
What individual Care providers can do to support TB Control

TB
Leading cause of death from a single agent Leading cause of death in women of child bearing years Leading cause of death in PLWAs 5000 individuals die each day One person is infected every second
3600 will be infected during this lecture

Dynamics of TB and HIV in Kenya

TB incidence/100,000
170 150 130 15 110 90 70 50 1975 10
TB HIV HIV-Nairobi

25 20

5
0 2000

1980

1985

1990

1995

HIV pevalence adults (%)

190

30

Critical Terminology
Exposure Infection Disease Contagion Everything at the bottom of the list requires those steps above it to occur; each step does not have to occur, however.

What do we know about TB/HIV?

No clear data that Patients with HIV have an increased chance of infection if exposed Patients with HIV have a higher risk of developing TB if TB infected
40% with recent exposure
Daley NEJM 1992;326:231-5

10% annually with LTBI

Selwyn NEJM 1989;320:545-50

What do we know about TB/HIV?

Patients with advanced HIV have an accelerated course from infection to disease
Time line infection to death as little as 12 weeks
Daley NEJM 1992;326:231-5

After initiating HAART for HIV, patients still have a higher rate of developing TB than an HIV negative patient
25% reduction in risk for every 100 CD4 increase
Lawn AIDS 2006;20:1605-12

WHO recommendations
Screen all TB patients for HIV Screen all HIV patients for TB

Screen for HIV in TB patients

Theoretically should be easy
HIV tests are easy to use HIV testing has high sensitivity and specificity The window period for false negative tests during seroconversion is short One time only unless new HIV risk factors identified Needs testing early in care ART eligible

Rates of HIV testing in TB Patients

Country China
Kenya Pakistan India

HIV testing rates 34%

94% 4% 56%

Why are reported testing rates so low?

Availability of test kits Availability of Counselors
Diagnostic Testing and Counseling Voluntary Counseling and Testing

Stigma Reticence of health Care Providers

Diagnosis of TB in HIV patients

More difficult for a variety of reasons Present state of the art for Testing for TB is poor
Latent TB Infection
Tuberculin skin testing or Interferon Gamma Release Assay

Active TB
Gold standard is based on identification of organism. Smear is insensitive Culture is often unavailable Even when culture is available, 20% of TB cases are culture negative and based on clinical presentation and the response to therapy

TB Diagnosis

Diagnosis of TB in HIV patients

Wide range of presentations for TB- The great masquerader
Extrapulmonary disease more common in HIV patients Smear negative disease is more common in HIV patients Culture positive TB with a normal chest radiograph clearly occurs The window of opportunity to diagnose TB is shortened Challenge is to think TB on every interaction with the HIV patient

Challenges in TB Diagnosis in HIV

Tanzania
Screening for a Vaccine trial HIV + patients CD4 <200, n=93 14 had clinical TB 4 had subclinical TB
AFB+/culture + but no symptoms and normal CXR

6 had no symptoms
Culture +
Mtei L. Clin Infect Dis 2005;40:1500-7

Algorithm for TB Screening in HIV+ Persons

1,748 HIV+ persons in Cambodia, Thailand, and Vietnam TB diagnosed in 267 (15%) Presence of cough for > 2-3 weeks during the preceding 4 weeks:
22-33% sensitive 82-88% specific

Presence of at least one (cough any duration, fever any duration, night sweats for > 3 weeks in preceding 4 wks)
93% sensitive 36% specific 97% negative predictive value
Cain NEJM 2010;362(8)
Cain KP. N Engl J Med 2010;362:707-16.

Screen for TB and HIV?

TB patients
All TB patients should be screened for HIV Theoretically not difficult
Rapid HIV testing or standard Elisa/western blot Sensitivity and specificity of testing is high

HIV patients
All HIV patients should be screened for TB More difficult
TB infection versus TB disease Diagnostic testing more challenging

One time only unless new HIV risk factors identified Needs testing early in care ART eligible

Repeatedly performed
Risk continues for both TB infection/reinfection and disease as long as patient lives in high incidence region

Treatment Issues

Challenges of Concomitant TB/HIV Treatment

Is it necessary to Treat Concomitantly?

Retrospective Studies Madrid* Meta-analysis of 6934 patients
63% increase in survival amongst patients initiating ART during TB therapy

Thailand** study of 1003

20 X greater mortality risk in patients receiving only TB compared to those receiving ART/TB
*Velasco et. al. JAIDS 2009;50:148-52. **Manosuthi et. al. JAIDS 2006;43:42-6.

Is it necessary to Treat Concomitantly?

Prospective, open label, randomized Control trial, South Africa Three arms
start ARV (EFV, dDI, 3TC) within 4 weeks of starting TB therapy start ARV within 4 weeks of continuation phase of TB therapy start ARV within 4 weeks of completing TB therapy

Arm 3 halted after enrollment complete

N Engl J Med 2010;362:697-706.

 Reduction in mortality in combined treatment versus sequential therapy

5.4 deaths/100 person years group 1 and 2 12.1 deaths/100 person years group 3
hazard ratio in the combined integrated-therapy groups, 0.44 95% confidence interval, 0.25 to 0.79; P = 0.003

Mortality lower in all cd4 stratifications Adverse events in groups were not different

Need to start but When?

Retrospective study, Spain
313 patients Lower mortality (9 vs 20%) in patients started on ART within 2 months of TB therapy*
Patients with CD 4 <100 Initiate ART at 2 weeks after starting TB rather than 8 weeks reduced mortality Iran had no significant difference in adverse effects including IRIS

Retrospective study,

WHO current guidelines recommend starting ARV therapy between 2 and 8 weeks in patients with CD4 of <200 cells/mm3 and during continuation phase in those with CD4 counts 200-350
*Velasco et al JAIDS 2009;50:148-152. **Tabarsi et al J Int AIDS Soc 2009;12:14

Drug Pairing
TB Treatment Regimen: HRZE 2 HR 4 Rifampin Interaction:
Key site of interactions involving ARV and the rifamycins is the hepatic cytochrome P450-3A4 (CYP3A4) and 2B6 (CYP2B6) isoforms Induction of CYP3A4 and 2B6 by the rifamycins significantly reduces levels and exposure to the PIs and NNRTIs Rifampin >>> Rifabutin > Rifapentine
Rifapentine use has been associated with R resistant TB relapse Intermittent dosing with Rifabutin may lead to R Resistant TB relapse

What can be used with Rifampin? (What is not effected by the P450 cytochrome system)
NRTIs- all Ok NNRTIs
Efavirenz is best and least effected Conflicting data about Nevirapine so would NOT be first choice

PIs
All go through the Cytochrome P450 system Only boosted PIs are possible but risk of hepatitis and/or intolerance is high

The Dreaded Complication Immune Reconstitution Inflammatory Syndrome

Effect of HAART on TB risk

Overall, immune reconstitution due to HAART decreases, not increases, TB risk

Jones JL. Int J Tuberc Lung Dis 2000;4:1026AASD Badri M. Lancet 2002;359:2059-64

Schematic representation of the different forms of TB-associated IRIS and ARTassociated TB

Previously undiagnosed prevalent TB Newly-acquired TB Progression of sub-clinical TB present before ART (reactivation) A sub-set have IRIS

Meintjes G. Lancet Infect Dis 2008. Lawn SD. AJRCCM 2008. Manabe Y. J Infect Dis 2009.

TB Adenitis/IRIS

WHO Programmatic Issues for TB/HIV The Three Is

Intensified Case Finding Isoniazid Preventive Therapy Infection Control

Intensified Case Finding

Physician
Screen every patient with TB for HIV Screen every HIV patient for TB
At every encounter

Program
Promotion of Universal HIV testing Removal of system barriers to access care and early screening for TB

HAART and INH

TB Prevention in HIV
Rio de Janeiro, Brazil 11,026 HIV + persons receiving care at 29 public clinics, Sept 2003-Sept 2005 Intervention No HAART/no INH HAART INH HAART and INH

TB per 100 p-y 4.01 1.90 1.27 0.80

After adjusting for age, previous TB, and baseline CD4, 76% in TB risk if received HAART and INH compared to no HAART/no INH

Golub J. AIDS 2007;21:1441-8.

HAART and INH

TB Prevention in HIV
Urban and rural South Africa 2,778 HIV + persons receiving care at 2 hospital-based clinics, June 2003-Dec 2007 Intervention No HAART/no INH HAART INH HAART and INH TB per 100 p-y 7.1 4.6 5.2 1.1

After adjusting for age, sex, clinic location, and baseline CD4: 64% in TB risk if received HAART; 89% in TB if received ART after INH
Golub J. AIDS 2009;23:631-6.

Algorithm for TB Screening in HIV+ Persons

1,748 HIV+ persons in Cambodia, Thailand, and Vietnam TB diagnosed in 267 (15%) Presence of cough for > 2-3 weeks during the preceding 4 weeks:
22-33% sensitive 82-88% specific

Presence of at least one (cough any duration, fever any duration, night sweats for > 3 weeks in preceding 4 wks)
93% sensitive 36% specific 97% negative predictive value
Cain NEJM 2010;362(8)
Cain KP. N Engl J Med 2010;362:707-16.

Infection Control
Administrative Controls
Early Detection Effective Therapy for TB
Ensure completion of therapy

Environmental Controls
Ventilation Ultraviolet light

Personal Respiratory Devices

Least effective and least studied

Conclusions
To treat TB and HIV adequately, the first step is improved diagnosis. Concomitant therapy reduces mortality timing of treatment is the challenge ( during TB induction phase is clear) IRIS, through a risk, is not a reason to not start ART. Intensified case finding is necessary to reduce community burden and transmission. Early diagnosis and initiation of therapy is the best infection control.

The International Union Against TB and Lung Disease Health Solutions for the Poor www.theunion.org

Questions?